Compounds and method for blocking transmission of malarial parasite

Abstract

Disclosed are compounds of formula (I) and formula (II): (I) (II) wherein R 1 , R 2 , A, and B are as defined herein. Also disclosed is a method of blocking transmission of a Plasmodium parasite and a method of treating or preventing malaria comprising administering to an animal an effective amount of a first compound of formula (I) or (II) either alone or in combination with a second compound selected from elesclomol, NSC174938, NVP-AUY922, Maduramicin, Narasin, Alvespimycin, Omacetaxine, Thiram, Zinc pyrithione, Phanquinone, Bortezomib, Salinomycin sodium, Monensin sodium, Dipyrithione, Dicyclopentamethylene-thiuram disulfide, YM155, Withaferin A, Adriamycin, Romidepsin, AZD-1152-HQPA, CAY10581, Plicamycin, CUDC-101, Auranofin, Trametinib, GSK-458, Afatinib, and Panobinostat.

The invention claimed is: 
     
       1. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein A is CH, 
         B is CR 3 ═CR 4 , 
         R 1  is selected from 4-methylsulfonylphenyl, 4-ethylsulfonylphenyl, 2-methyl-4-methylsulfonylphenyl, and 3-piperazinylmethyl-4-methylsulfonylphenyl, 
         R 2  is selected from 4-chlorophenyl, 4-fluorophenyl, 3-cyano-4-chlorophenyl, 3-hydroxy-4-chlorophenyl, 3-amino-4-chlorophenyl, 4-aminomethylphenyl, and 3-methoxy-4-chlorophenyl, 
         R 3  and R 4  are independently selected from hydrogen, hydroxyl, OR 5 , halogen, optionally substituted C 6-10  aryl, and optionally substituted C 1-6  alkyl, and 
         R 5  is C 1-12  alkyl, C 6-10  aryl, halogen, or hydroxyl, 
         or a pharmaceutically acceptable salt thereof. 
       
     
     
       2. The compound or salt of  claim 1 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       3. A compound of formula (I): 
       
         
           
           
               
               
           
         
         wherein A is CH, B is CR 3 ═CR 4 , R 2  is selected from 4-chlorophenyl, 4-fluorophenyl, 4-dimethylaminomethylphenyl, 3-methylphenyl, 3-methoxyphenyl, 3-cyanophenyl, phenyl, 5-indolinone, 5-isoindolinone, 3-cyano-4-chlorophenyl, 4-cyanophenyl, 4-(2-dimethylaminoethyl)phenyl, 4-azetidinylphenyl, and 4-ethylphenyl, 2-amino-5-pyridyl, and R 1  is selected from 4-morpholinocarbonylphenyl, 4-dimethylaminocarbonylphenyl, 4-(3,5-dimethylaminomorpholino)carbonylphenyl, 4-(4-methylpiperazinyl)carbonylphenyl, 4-piperazinylcarbonylphenyl, 4-piperidinylcarbonylphenyl, 4-cyclopentylaminocarbonylphenyl, 4-azetidinylcarbonylphenyl, 4-(4-hydroxyethylpiperazinyl)carbonylphenyl, 4-(N-methyl-N-cyclopropylamino)carbonylphenyl, 4-cyclobutylaminocarbonylphenyl, 2-trifluoroethylaminocarbonylphenyl, 4-(2-dimethylaminoethylaminocarbonyl)phenyl, 4-(4-[2-dimethylaminoethyl]piperazin-1-yl-carbonyl)phenyl, 4-cyclopropylaminocarbonylphenyl, 4-(1-[2-dimethylaminoethyl]piperidin-4-amino)carbonylphenyl, 4-(N-(1-(2-hydroxyethyl)azetidin-3-ylamino)carbonylphenyl, and 4-(pyrrolidinyl-3-amino)carbonylphenyl, 
         R 3  and R 4  are independently selected from hydrogen, hydroxyl, OR 5 , halogen, optionally substituted C 6-10  aryl, and optionally substituted C 1-6  alkyl, and 
         R 5  is C 1-12  alkyl, C 6-10  aryl, halogen, or hydroxyl. 
       
     
     
       4. The compound or salt of  claim 3 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
       5. A pharmaceutical composition comprising a compound or salt of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
       6. A method of blocking transmission of a  Plasmodium  parasite or treating malaria by killing or arresting the growth of  Plasmodium  organisms in a mammal, wherein the  Plasmodium  organisms are in a gametocyte stage comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a first compound of  claim 1 , optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat. 
     
     
       7. A pharmaceutical composition comprising a compound or salt of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
       8. A method of blocking transmission of a  Plasmodium  parasite or treating malaria by killing or arresting the growth of  Plasmodium  organisms in a mammal, wherein the  Plasmodium  organisms are in a gametocyte stage comprising administering to a mammal in need of such treatment, a therapeutically effective amount of a first compound of  claim 3 , optionally in combination with an antimalarial compound selected from elesclomol, NSC174938, NVP-AUY922, maduramicin, narasin, alvespimycin, omacetaxine, thiram, zinc pyrithione, phanquinone, bortezomib, salinomycin sodium, monensin sodium, dipyrithione, dicyclopentamethylene-thiuram disulfide, YM155, withaferin A, adriamycin, romidepsin, AZD-1152-HQPA, CAY10581, plicamycin, CUDC-101, auranofin, trametinib, GSK-458, afatinib, and panobinostat.